NEJM: Rivaroxaban may be good alternative to warfarin

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As the race to find newer, safer anticoagulants that are better alternatives to warfarin continues, a study in the Aug. 10 issue of the New England Journal of Medicine showed that rivaroxaban may provide some competition and could be effective in preventing stroke in atrial fibrillation (AF) patients.

While warfarin works and has been shown to reduce stroke in AF patients by one-half to two-thirds, it does so at an increased risk of bleeding. Additionally, warfarin treatment often requires frequent monitoring and dose adjustments.

"Rivaroxaban is a direct factor Xa inhibitor that may provide more consistent and predictable anticoagulation than warfarin," Manesh R. Patel, MD, of the Duke University School of Medicine in Durham, N.C., and colleagues wrote.

During the double-blind ROCKET AF (Rivaroxaban Once daily oral direct factor Xa inhibitor Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) study, Patel and colleagues enrolled 14,264 AF patients with a history of stroke or other independent risk factors for future stroke to compare whether rivaroxaban may be a safe alternative to warfarin. Patients in the trial were randomized to receive either a 20 mg daily dose of rivaroxaban (7,131 patients) or dose-adjusted warfarin (7,133 patients).

“Warfarin has been a standard treatment for decades, but requires a rigorous monitoring schedule to ensure therapeutic dosing levels, and is subject to the potential of food and drug interactions that present treatment obstacles for patients and doctors alike,” Patel, the study’s lead author, stated in a press release.

Patel and colleagues found that rivaroxaban was non-inferior to warfarin and showed a nonsignficant trend toward benefit compared to warfarin. The primary outcome (stroke or systemic embolism) occurred in 188 patients in the rivaroxaban group and 241 patients in the warfarin group. Primary events occurred in 189 patients in the rivaroxaban group and 243 patients in the warfarin group. Among patients within the intention-to-treat analysis, 269 patients in the rivaroxaban experienced primary events compared to 306 patients in the warfarin group. Additionally, the researchers found that rates of bleeding and adverse events were similar between both groups.

Major and non-major clinically relevant bleeding events occurred in 1,475 patients in the rivaroxaban group (14.9 percent per year) and 1,449 patients in the warfarin group (14.5 percent per year). Rates of major bleeding were comparable for rivaroxaban and warfarin, 3.6 percent per year vs. 3.4 percent per year.

Patients in the rivaroxaban arm also experienced fewer intracranial hemorrhages compared with those in the warfarin arm, 0.5 percent vs. 0.7 percent. Critical organ bleeds and bleeding-related deaths were also lower in the group administered rivaroxaban, 0.8 percent vs. 1.2 percent and 0.2 percent vs. 0.5 percent, respectively.

However, patients in the rivaroxaban arm did experience increased rates of hemoglobin/hematocrit drop and transfusions compared to those who were administered warfarin.

The researchers said that while patients within the trial were at an increased risk for bleeding events, the rates of major bleeds were similar to recent studies involving AF patients.

“Atrial fibrillation is becoming increasingly prevalent and can be life-threatening if not properly managed. Stroke prevention is a key treatment goal in atrial fibrillation management,” stated co-author of the study Keith A. A. Fox, MB, ChB, professor of cardiology at the Centre for Cardiovascular Science University and Royal Infirmary of Edinburgh in Edinburgh, Scotland. “Rivaroxaban appears to be an attractive and well-tolerated clinical alternative to warfarin for patients with atrial fibrillation.”

In an accompanying editorial, Gregory J. del Zoppo, MD, and Misha Eliasziw, PhD, of the University of Washington School of Medicine in Seattle, and the University of Calgary in Calgary, Alberta, Canada, respectively, outlined why the search for newer anticoagulants is so important. “Although guidelines suggest a target international normalized ratio (INR) of 2.5 (range, 2.0 to 3.0) for this indication, only about 60 percent of patients have an INR within the recommended range at a given time in usual clinical practice,” del Zoppo and Eliasziw noted as the major limitation of warfarin.

“For the management of atrial fibrillation, oral alternatives to warfarin have arrived,” stated del Zoppo and Eliasziw. “Their simplicity of use is attractive, and they appear to have an efficacy similar to that of warfarin, with the proviso that comparisons seem to depend on how easily the patient can be treated with warfarin.”

However, del Zoppo and Eliasziw did offer that a concern of trials such as this and the RE-LY trial is that these types of trials do not address “the absence of antidotes to rapidly reverse the anticoagulant effects of either rivaroxaban or dabigatran in the case of life-threatening hemorrhage or surgery.”

Del Zoppo and Eliasziw concluded that more studies will be needed to better tailor therapies in hopes of preventing stroke in this AF patient population.

The trial was funded by Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare.